Cooperative Binding in a Phosphine Oxide-Based Halogen Bonded Dimer Drives Supramolecular Oligomerization

Article abstract of DOI:10.1021/acs.joc.6b02822

Triphenylphosphine oxide forms halogen-bonded (XB) complexes with pentafluoroiodobenzene and a 1,4-diaryl-5-iodotriazole. The stability of these complexes is assessed computationally and by ³¹P NMR spectroscopy in toluene-d₈ solution, where both complexes are weakly associated. This knowledge is applied to the design and synthesis of two self-complementary phosphine oxide-iodotriazole hybrids that incorporate a phosphine oxide XB acceptor and a 1,4-diphenyl-5-iodotriazole XB donor within the same molecule. The self-complementary design of these modules facilitates their assembly in both toluene-d₈ and, surprisingly, DCM-d₂ into dimers, with significant stabilities, through the formation of halogen-bonded diads. The stability of these assemblies is a result of significant levels of cooperative binding that is present in both solvents. The connection of two of these hybrid units together, using a flexible spacer, facilitates the aggregation of these modules in DCM-d₂ solution, through halogen bonding, forming oligomeric assemblies.

Full text of DOI:10.1021/acs.joc.6b02822

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Article
Cooperative binding in a phosphine oxide-based halogen
bonded dimer drives supramolecular oligomerization
Leonardo Maugeri, Tomas Lebl, David B. Cordes, Alexandra M. Z. Slawin, and Douglas Philp
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02822 • Publication Date (Web): 20 Jan 2017
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The Journal of Organic Chemistry
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Cooperative binding in a phosphine oxide-based halogen bonded di-
mer drives supramolecular oligomerization
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Leonardo Maugeri, Tomáš Lébl, David B. Cordes, Alexandra M. Z. Slawin and Douglas Philp*
EaStChem and School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, United Kingdom
ABSTRACT: Triphenylphosphine oxide forms halogenꢀbonded (XB) complexes with pentafluoroiodobenzene and a 1,4ꢀdiarylꢀ5ꢀ
iodotriazole. The stability of these complexes is assessed computationally and by 31P NMR specꢀ
troscopy in d8ꢀtoluene solution, where both complexes are weakly associated. This knowledge is
applied to the design and synthesis of two selfꢀcomplementary phosphine oxideꢀiodotriazole hybrids
that incorporate a phosphine oxide XB acceptor and a 1,4ꢀdiphenylꢀ5ꢀiodotriazole XB donor within
the same molecule. The selfꢀcomplementary design of these modules facilitates their assembly in
both d8ꢀtoluene and, surprisingly, d2ꢀDCM into dimers, with significant stabilities, through the forꢀ
mation of halogenꢀbonded diads. The stability of these assemblies is a result of significant levels of
cooperative binding that is present in both solvents. The connection of two of these hybrid units
together, using a flexible spacer, facilitates the aggregation of these modules in d2ꢀDCM solution,
through halogen bonding, forming oligomeric assemblies.
The last 30 years has seen an explosion of nonꢀcovalent asꢀ
semblies that are stabilized through the concatenation of hyꢀ
drogen bond donors and acceptors into contiguous diads,15
triads16 and tetrads,17 giving rise to a rich diversity of supramoꢀ
lecular oligoꢀ and polymeric assemblies that are stable in soluꢀ
tion. However, this approach to the construction of nonꢀ
covalent assemblies stabilized by halogen bonds is still in its
infancy. Our laboratory has developed selfꢀcomplementary
diads that exploit the XB donating properties of 1,4ꢀdiphenylꢀ
5ꢀiodotriazoles and their interaction with both neutral nitroꢀ
gen18 and charged oxygen19 XB acceptors to afford halogenꢀ
bonded dimers with measurable stability in organic solvents.
Systems that bear a formal charge present a particular design
challenge when considering selfꢀcomplementary structures, as
these assemblies suffer inherently through their design from
significant electrostatic repulsion. In this work, we describe an
optimized selfꢀcomplementary dimeric design that features an
iodotriazole XB donor and a triphenylphosphine oxide as the
XB acceptor. Phosphine oxides incorporate an acceptor atom
that bears a formal charge within a functional group that is
neutral overall. Therefore, this functional group represents an
excellent compromise between weak, neutral XB acceptors,
such as pyridine, and charged phenoxide XB acceptors, which
introduce significant electrostatic repulsion when incorporated
within homodimeric assemblies. Despite the fact that Rissanen
and coꢀworkers have highlighted20 the potential of Nꢀoxides as
XB acceptors in solution recently, there are few fundamental
studies that focus on XBs formed between Nꢀoxides21 or phosꢀ
phine oxides22 and typical XB donors, especially in solution.
Here, we report the computational and experimental assessꢀ
ment of the interaction between triphenylphosphine oxide and
neutral XB donors. This knowledge is applied to the design
and synthesis of selfꢀcomplementary phosphine oxideꢀ
INTRODUCTION
Over the last two decades, the halogen bond (XB) – the
noncovalent interaction1 between an electronꢀdeficient halogen
atom and a Lewis base – has evolved from a weak intermolecꢀ
ular interaction of largely academic curiosity usually discussed
in the context of solid state structures to a fullyꢀfledged memꢀ
ber of the supramolecular toolkit. Undoubtedly, this dramatic
change is a result of the seminal work of the group of Metranꢀ
golo and Resnati2 and others3 during the late 1990s and early
2000s. Today, XB interactions are employed in many fields of
the chemical sciences, e.g. crystal engineering,4 medicinal
chemistry,5 materials chemistry,6 nanoscience.7 Fundamental
studies8 have highlighted how single point XB complexes
between wellꢀstudied classes of neutral donors and acceptors
in the solid state are generally weak when transferred to soluꢀ
tion. Therefore, the creation of functional XBꢀbased supramoꢀ
lecular assemblies that are stable in solution requires complexꢀ
es between XB donors and acceptors with far higher intrinsic
stabilities than those involved in classical, solid state studies.
Several research groups have circumvented these limitations
by implementing cationic XB donors within organic strucꢀ
tures, thus realizing a variety of molecular scaffolds able to
perform as sensors9 and supramolecular catalysts10 through
chargeꢀassisted halogen bonding. An alternative strategy to
overcome the limited stability of single point neutral XB interꢀ
actions involves exploiting cooperativity.11 The design of triꢀ
meric,12 tetrameric,13 even polymeric14 XB donors, based on
the iodoperfluorobenzene unit, able to interact with compleꢀ
mentary multidentate XB acceptors has allowed the realization
of multipoint XB complexes with stability constants comparaꢀ
ble to those shown by conventional noncovalent interactions in
solution.
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iodotriazole hybrid –incorporating both a phosphine oxide XB
able to promote the formation22a of cocrystals with a variety of
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acceptor and a 1,4ꢀdiphenylꢀ5ꢀiodotriazoles XB donor within
the same molecule. This module is capable of homodimerizaꢀ
tion as a halogen bonded diad in both d8ꢀtoluene and d2ꢀDCM
and this assembly exhibits significant levels of cooperative
binding in both solvents. The connection of two of these hyꢀ
brid units together, using a flexible spacer, facilitates the agꢀ
gregation of these modules in solution, through halogen bondꢀ
ing, forming oligomeric assemblies.
XB donors that are otherwise hard to crystallize. In solution,
on the other hand, only a handful of association constants have
been reported for XB complexes formed between phosphine
oxides, acting as the XB acceptor and XB donors, such as
perfluorohalocarbons8b,23 (PFHCs) and phenyliodoacetyꢀ
lenes.8d
In order to facilitate the design of more complex structures,
we initially probed the structure and bonding in simple comꢀ
plexes formed between triphenylphosphine oxide TPPO and
perfluoroiodobenzene PFIB and model iodotriazole ITZ. We
performed a series of calculations on the [PFIB•TPPO] and
[ITZ•TPPO] complexes in toluene solution at the
TPSSh/def2ꢀTZVP level of theory. The geometries and stabiliꢀ
ties of the two complexes are shown in Figure 1a.
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RESULTS AND DISCUSSION
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The ability of phosphine oxides to accept halogen bonds has
been well documented22a–d in the solid state. The highly polarꢀ
ized nature of the phosphorusꢀoxygen bond renders the oxygen
atom a strong Lewis base and, thus, a powerful XB acceptor
Figure 1. (a) Geometric parameters and calculated enthalpies of complexation (numbers in bold type, in kJ at 298 K) for the
complexes [PFIB•TPPO] and [ITZ•TPPO]. (b) Visualization of the nonꢀcovalent interactions present in the complexes
[PFIB•TPPO] and [ITZ•TPPO]. Left: Intermolecular interaction isosurfaces generated by NCIPLOT24 for s = 0.5 and –0.05 <
sign(λ2)ρ < 0.05 (colour scale: attractive (blue) → repulsive (red)). Right: Plots of sign(λ2)ρ vs. reduced gradient highlighting the
favourable interaction corresponding to the halogen bond at sign(λ2)ρ ~ –0.035. Atom colouring: C atoms = gray, N atoms = blue,
O atoms = red, I atoms = purple, P atoms = orange. H atoms omitted for clarity. (c) Visualization of the n →
in the [PFIB•TPPO] complex. Equivalent interactions are also present in the [ITZ•TPPO], see Supporting Information.
σ* interactions present
Both complexes have enthalpies of complexation that are
significantly negative at 298 K. The O•••I distances in both
complexes are similar – [PFIB•TPPO], d(O•••I) = 2.782 Å
and [ITZ•TPPO], d(O•••I) = 2.776 Å – and are significantly
less than the sum of the van der Waals radii for O and I (Σvdw
= 3.50 Å). These distances are similar to those calculated19 at
the same level of theory for neutral XB acceptors, such as the
oxygen atom in 4ꢀpyridone (d(O•••I) ~ 2.80 Å), and signifiꢀ
cantly larger than those associated with anionic acceptors,
such as a phenoxide oxygen atom (d(O•••I) ~ 2.50 Å). As exꢀ
pected, analysis of the reduced gradient24 of the electron densiꢀ
ty (Figure 1b) reveals significant low density, low gradient
regions associated with the both complexes that are signifiꢀ
cantly attractive (sign(λ2)ρ ~ –0.03).
nonꢀbonding orbitals on the O atom of the phosphine oxide
acceptor and the σ* orbital associated with the C–I bond. Natꢀ
ural bond analysis (NBO) analysis25 (Figure 1c) reveals that
the observed geometry is, in part, a result of the interplay beꢀ
tween n → σ* donation associated with two of the lone pairs is
present on the phosphine oxide and these interactions result in
a deviation of the P–O•••I angle observed in the complexes
away from 180°.
In order to provide an experimental baseline for our studies,
we first measured the association between perfluoroiodobenꢀ
zene PFIB (the XB donor) and triphenylphosphine oxide
TPPO (the XB acceptor) in d8ꢀtoluene solution at 295 K. The
strength of this interaction in solution can be measured readily
using 31P NMR spectroscopy as the phosphorus chemical shift
is particularly sensitive22d to the formation of a halogen bond.
Accordingly, TPPO was titrated with increasing amounts of
PFIB in d8ꢀtoluene at 295 K and a 121.3 MHz 31P NMR specꢀ
trum recorded at each titration step. Upon addition of PFIB,
We were intrigued by the geometry of these complexes in
which the P–O bond in the XB acceptor subtends an angle of
around 150° to the C–I bond in the XB donor. This geometry
is readily understood in terms of the significant donation from
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The Journal of Organic Chemistry
the 31P resonance of TPPO was shifted significantly downꢀ
TPPO behaves in a very similar manner to other neutral XB
acceptors when interacting with neutral XB donors.
field (ꢁδ(31P) > +1.40; [TPPO] = 10 mM; [PFIB] = 500 mM).
These data were fitted26 to a 1:1 binding model for the comꢀ
plex [PFIB•TPPO] affording (see Supporting Information for
details) a stability constant for this complex of 2.7 ± 0.3 M–1 in
d8ꢀtoluene at 295 K. Chemical shift changes that arise from
nonꢀspecific interactions associated with the addition of high
concentrations of PFIB were discounted by repeating the exꢀ
periment, adding hexafluorobenzene instead of PFIB. In this
case, the observed chemical shift change was much smaller
(−0.22 ppm) and in an upfield, rather than a downfield, direcꢀ
tion (see Supporting Information for further details).
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Chelate cooperativity has been used successfully in several
contexts27 for creating stable, supramolecular assemblies in
solution using hydrogen bonds. In terms of XB interactions,
similar exploitation12,13,18,19 of cooperativity is in its infancy.
With the aim of exploiting cooperative binding within a hoꢀ
modimeric assembly, we designed compound 2, which bears
both an XB donor (the iodotriazole) and an XB acceptor (the
phosphine oxide).
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The calculated structure (TPSSh/def2TZVP) of the [2•2]
homodimer (Figure 2) is approximately centrosymmetric and
is characterized by two short I•••O–P XB contacts – d(O•••I) =
F
2.771 Å and d(O•••I) = 2.768 Å and ∠(O•••I–C) = 179.8°. The
N N
F
calculated enthalpy for the formation of the homodimer in
toluene at 298 K is −53.8 kJ. Examination of the reduced graꢀ
dient of the electron density in dimer [2•2] reveals two low
density, low gradient regions between the O and I atoms assoꢀ
ciated with the halogen bonds (pale blue, Figure 2) and some
additional weakly attractive, van der Waalsꢀlike areas of interꢀ
actions along the spine of the dimer (green, Figure 2). Natural
Bond Orbital (NBO) analysis25 of the [2•2] dimer reveals that
the sum of the second order perturbation energies for the interꢀ
actions between the lone pairs located on the phosphine oxide
and the σ* orbitals associated with the iodotriazole two C–I
bonds are 36.4 kJ, suggesting that this interaction could play a
relatively important role in stabilizing the homodimer.
N
F
I
F
F
1
Iodotriazole 2 was synthesized readily, starting from (4ꢀ
ethynylphenyl)diphenylphosphine oxide 3, (Scheme 1). Ioꢀ
dination of alkyne 3 was achieved by treatment with Nꢀiodo
morpholinium iodide using a modification of the procedure
described28 by Sharpless and Fokin. The copperꢀcatalyzed
cycloaddition between iodoalkyne 4 and pentafluorophenyl
azide 5, in the presence of the tris((1ꢀbenzylꢀ1Hꢀ1,2,3ꢀtriazolꢀ
4ꢀyl)methyl)amine TBTA, afforded the target phosphine oxide
2 in 31% overall yield starting from 3.
Scheme 1.
Figure 2. Connecting a triphenylphosphine oxide XB acceptor to
an iodotriazole XB donor results in compound 2 that is capable of
associating to form a homodimer stabilized by two halogen bonds.
The geometry of this dimer at the TPSSh/def2ꢀTZVP level of
theory reveals an almost centrosymmetric dimer with d(O•••I) =
2.771 Å and d(O•••I) = 2.768 Å. Intermolecular interaction isosurꢀ
faces generated by NCIPLOT24 for s = 0.5 and –0.05 < sign(λ2)ρ
< 0.05 (colour scale: attractive (blue) → repulsive (red)) highꢀ
lights the favourable interaction corresponding to the halogen
bond at sign(λ2)ρ ~ –0.05 (pale blue isosurface). Atom colouring:
C atoms = gray, N atoms = blue, O atoms = red, F atoms = green,
P atoms = orange, I atoms = purple. H atoms are omitted for clariꢀ
ty.
When this titration was repeated, using 4ꢀ(3,5ꢀdiꢀtertꢀ
butylphenyl)ꢀ5ꢀiodoꢀ1ꢀ(perfluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazole
1
as the XB donor, a similar pattern of chemical shift changes
was observed for the 31P resonance of TPPO (ꢁδ(31P) > +2.00;
[TPPO] = 10 mM; [1] = 0 – 200 mM). In this instance, fitting
of these data to a 1:1 binding model for the complex
[1•TPPO] afforded (see Supporting Information for details) a
stability constant of 6.0 ± 0.3 M–1 in d8ꢀtoluene at 295 K. In
common with other XB interactions in solution, these associaꢀ
tion constants are rather small and these results suggest that
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In order to assess the ability of 2 to homodimerize in soluꢀ
Page 4 of 10
tion, a 31P NMR dilution experiment in d8ꢀtoluene at 295 K
was performed. Sadly, the poor solubility of iodotriazole 2 in
this solvent – a saturated solution has a concentration of less
than 2 mM – limited the range of dilution experiments that
could be performed using 31P NMR spectroscopy. Despite the
observations of small chemical shift changes in the 202.4 MHz
31P NMR spectrum of 2 upon dilution of a 1.5 mM solution in
d8ꢀtoluene at 295 K to 0.5 mM, the stability of homodimer
[2•2] could not be determined from these data. We reasoned
that, in order to fully exploit the homodimeric binding motif
shown in Figure 2, a more soluble version of iodotriazole 2
had to be designed. This redesign focused on the replacement
of the fluorine atom in the para position of the pentafluoroꢀ
phenyl ring in 2 with an nꢀoctyl ester group. Iodotriazole 6
could be synthesized using identical methodology to that deꢀ
scribed previously (Scheme 2). Esterification of commercially
available pentafluorobenzoyl chloride 7 with nꢀoctanol in THF
afforded ester 8. Subsequently, the SNAr reactivity29 of the 4ꢀ
position of a monosubstituted pentafluorophenyl ring was
exploited to introduce the azide group into the aromatic ring
by reacting 8 with sodium azide in an acetoneꢀwater mixture
(1:1) affording the 1,4ꢀdisubstituted tetrafluorobenzene 9. The
final cycloaddition step between azide 9 and iodoalkyne 4 in
presence of the copper(I)ꢀTBTA complex allowed the facile
preparation of the target iodotriazole 6.
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Figure 3. Stick representation of the solidꢀstate structure of 6 deꢀ
termined from single crystal Xꢀray diffraction data. Atom colourꢀ
ing: C atoms = gray, N atoms = blue, O atoms = red, F atoms =
green, P atoms = orange, I atoms = purple.
The solubility of iodotriazole 6 in toluene was found to be
significantly better than that of 2 – a saturated solution of 6 in
this solvent has a concentration of more than 20 mM. This
improved solubility allowed us to carry out appropriate diluꢀ
tion experiments in d8ꢀtoluene in order to evaluate the stability
of the [6•6] homodimer. Significant upfield chemical shift
changes for the single phosphorus resonance were observed in
the 202.4 MHz 31P NMR spectra, recorded on a solution of 6
at increasing dilutions in d8ꢀtoluene from 20 mM down to
1 mM. These chemical shift changes were fitted to a dimerizaꢀ
tion binding model26 affording an association constant for the
formation of the homodimeric species [6•6] (Kdimer) of 174 ±
36 M–1 at 295 K in d8ꢀtoluene.
Scheme 2.
In order to establish the magnitude of cooperativity
achieved by connecting the phosphine oxide XB acceptor to
the iodotriazole XB donor within the [6•6] homodimer, we
quantified the effective molarity11 (EM) for binding within the
[6•6] homodimer and the associated connection free energy30
(∆GS). The measurement of the thermodynamic effective moꢀ
larity requires determination of an appropriate reference assoꢀ
ciation constant. In order to obtain this comparison data, iodoꢀ
triazole 10 (Figure 4a) was prepared by copperꢀmediated cyꢀ
cloaddition of azide 9 with (iodoethynyl)benzene. Measureꢀ
ment of the single point association constant Kref for the
[10•TPPO] complex at 295 K in d8ꢀtoluene by 31P NMR specꢀ
troscopy afforded a value of 5.6 ± 0.5 M–1 (Figures 4b). The
effective molarity for the formation of homodimer [6•6] can
then be evaluated30 from the ratio of Kdimer for the [6•6] hoꢀ
modimer to (Kref)2 – this calculation afforded a value of the
EM of 5.7 M and corresponds to a connection free energy,
∆GS, of 4.3 kJ mol–1. These values are similar to the largest
values reported27,31 for hydrogenꢀbonded dimers where EM
and ∆GS values are available.
Single crystals of 6, suitable for analysis by Xꢀray diffracꢀ
tion, were grown by slow evaporation of a concentrated soluꢀ
tion of 6 in acetonitrile. The solidꢀstate structure of 6 reveals
(Figure 3) an antiparallel orientation of the P–O bond in 6
with respect to the C–I bond within the same molecule and
this geometry results in the formation of halogenꢀbonded tapes
rather than discrete homodimeric assemblies. An analogous
crystal packing motif is also observed for iodotriazole 2 (see
Supporting Information). The halogen bonds present in the
solid state structure of 6 are short (d(O•••I) = 2.720 Å, 0.8 Å
shorter than ΣvdW) and linear (∠(O•••I–C) = 171.5°) and the
geometry is in excellent agreement with our calculations. In
addition, there are also short contacts (0.15 Å shorter than
ΣvdW) between the carbonyl oxygen atom of an ester group in
one molecule of 6 and the fluorinated aromatic ring of an adꢀ
jacent molecule in the crystal.
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iodotriazole 10 and XB acceptor TPPO. (ii) Partial 202.4 MHz
31P NMR spectra showing the progressive downfield shift obꢀ
served upon titrating a 10 mM solution of TPPO with increasing
amounts of iodotriazole 10 (0 to 150 mM) in d8ꢀtoluene at 295 K.
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Given the intrinsic stability of the [6•6] homodimer and its
ease of synthesis, we considered that our dimeric design could
be exploited as the noncovalent binding motif of a solutionꢀ
stable supramolecular polymer supported by halogenꢀbonded
dimers. Many laboratories have demonstrated32 supramolecuꢀ
lar polymerization driven by a variety of noncovalent interacꢀ
tions. All of these studies use the covalent connection of two
selfꢀcomplementary units using an appropriate spacer in order
to achieve polymerization. However, to the best of our
knowledge, this approach has never been applied to a solutionꢀ
stable supramolecular polymer based on XBs. In order to exꢀ
ploit the [6•6] homodimer in this context, we required that two
units of 6 be connected covalently. The most convenient way
of realizing this objective was linking the two carboxy termini
of 6 by a flexible pentamethylene spacer, affording the
bis(phosphine oxide) 11. Compound 11 was synthesized in
32% overall yield (Scheme 3) using similar methodology to
that employed previously.
Figure 4. (a) (i) Dimerization of the phosphine oxideꢀappended
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iodotriazole 6. (ii) Partial 202.4 MHz 31P NMR spectra showing
the progressive upfield shift observed upon dilution of a 20 mM
solution of iodotriazole 6 down to 2.5 mM in d8ꢀtoluene at 295 K.
(b) (i) Formation of the single point XB complex between model
Scheme 3.
In common with iodotriazole 2, compound 11 displayed
very poor solubility in d8ꢀtoluene – a saturated solution of 11
in this solvent has a concentration below 2 mM. Fortuitously,
however, 11 is freely soluble in d2ꢀDCM – solutions with conꢀ
centrations of up to 500 mM can be prepared readily at room
temperature. Therefore, we performed an experiment in which
a solution of 11 in d2ꢀDCM at 298 K was diluted from a startꢀ
ing concentration of 500 mM to 1 mM in eight steps and the
chemical shift of the single 31P resonance arising from 11 was
determined by 202.4 MHz 31P NMR spectroscopy at each step.
There is a significant upfield shift of this resonance from 28.5
ppm at 500 mM to 27.0 ppm at 1 mM. In addition, the single
31P resonance arising from 11 is relatively broad at high conꢀ
centrations, becoming progressively sharper upon dilution.
The upfield shift, together with the concomitant sharpening of
the 31P resonance observed upon dilution, suggests the forꢀ
mation of molecular aggregates of 11, stabilized by halogen
bonds, that are larger than the dimer [11•11].
In order to evaluate this hypothesis, it is necessary to underꢀ
stand the behavior of the core intermolecular interaction drivꢀ
ing the oligomerization of 11, namely the homodimerization
of the phosphine oxideꢀiodotriazole hybrid modules, in d2ꢀ
DCM solution. Since 11 is a covalently linked dimer of 6, this
process can be modelled readily by studying the assembly of
homodimer [6•6] in d2ꢀDCM. Halogen bonds formed between
neutral organic XB donors and acceptors usually have limited
stabilities8b,23 in halogenated solvents such as d2ꢀDCM. Thereꢀ
fore, we firstly assessed the formation of the single point XB
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complex [10•TPPO] in d2ꢀDCM. The addition of increasing
Page 6 of 10
1
amounts of iodotriazole 10 (from 1 to 10 equivalents) to a 5
mM solution of TPPO in d2ꢀDCM resulted in minimal changꢀ
es in the chemical shift of the 31P resonance of the XB accepꢀ
tor (TPPO) – the maximum chemical shift change observed
was only 0.13 ppm. This result indicates that the [10•TPPO]
complex is only very weakly bound in d2ꢀDCM and it was
impossible to fit this chemical shift data to a 1:1 binding modꢀ
el for [10•TPPO]. By contrast, the 31P chemical shift changes
observed upon diluting a 200 mM solution of iodotriazole 6
down to 1 mM in d2ꢀDCM could be fitted readily to a dimeriꢀ
zation model for the formation of [6•6], affording an associaꢀ
tion constant of 3.4 ± 0.3 M–1 for this complex. This result is
somewhat surprising and confirms the presence of the cooperꢀ
ative effect that is the result of connecting the two XB partners
within one molecular module has on the overall stability of the
halogen bonded complex. Although the stability of the single
point [10•TPPO] complex could not be measured directly in
d2ꢀDCM, we can estimate its stability using the association
constant of homodimer [6•6] in d2ꢀDCM. Assuming that the
effective molarity measured for the homodimerization of 6 in
d8ꢀtoluene is identical in d2ꢀDCM, the association constant of
the singly halogen bonded complex [10•TPPO] in d2ꢀDCM is
0.8 M–1, corresponding to half saturation concentration Kd of
1.25 M. This concentration is well beyond that which is accesꢀ
sible experimentally for these compounds. The determination
of the association constant for the dimer [6•6] at lower temꢀ
peratures revealed that, as expected, this complex becomes
more stable as the temperature is reduced – the association
constant for [6•6] increases from 3.2 ± 0.6 M–1 at 298 K to
8.8 ± 0.7 M–1 at 238 K. These data allowed us to extract therꢀ
modynamic parameters for [6•6] dimer in d2ꢀDCM, affording
values for ꢁH (– 9.3 kJ mol–1) and ꢁS (–2.6 J mol–1 K–1) of
binding. Therefore, the association of [6•6] is driven by a faꢀ
vorable enthalpic term, offset by a modestly unfavorable enꢀ
tropic contribution. These observations match8d,13b those of
other halogenꢀbonded systems where enthalpy and entropy
data are available. With this information in hand, we were now
able to construct a plausible model that describes the 31P NMR
chemical shift changes that are observed when solutions of 11
in d2ꢀDCM are diluted.
2
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Figure 5. (a) Isodesmic or equal K model of supramolecular
polymerization. The expected 31P chemical shift, δ(31P), can be
computed from the unbound chemical shift, δfree, the limiting
chemical shift difference between bound and unbound states,
ꢁδlimit, the association constant, K1, and [11]total. Best fits (dotted
lines) of the isodesmic model to 31P chemical shift data (filled
circles) for solutions of 11 in d2ꢀDCM at 278 K (b, left) and 295 K
(c, left). This model can also be used to predict the fraction of
species in solution at 278 K (b, right) and 295 K (c, right). Red
lines represent monomeric 11, blue lines represent the [11]2 dimer
and green lines represent oligomers of 11 containing three or
more monomer units. (d) Scanning electron micrograph of a samꢀ
ple of 6 deposited from a 20 mM solution in d2ꢀDCM at 298 K.
(e) Scanning electron micrograph of a sample of 11 deposited
from a 20 mM solution in d2ꢀDCM at 298 K.
Over the past 20 years, several models33 of nonꢀcovalent
polymerization have been developed. The simplest of these
models is the isodesmic or equal K model34 in which monomer
units are added sequentially and reversibly to the chain ends of
growing oligomers (Figure 5a) according to an equilibrium
model in which each chain extension step has the same equiꢀ
librium constant, K1.
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The Journal of Organic Chemistry
(perfluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazole18 (1), (4ꢀethynyl)diphenyl phosꢀ
We could obtain excellent fits (Figures 5b and 5c, left) for
phine oxide35 (3), Nꢀiodo morpholinium iodide,28 (tris((1ꢀbenzylꢀ1Hꢀ
1,2,3ꢀtriazoleꢀ4ꢀyl)methyl) amine36 (TBTA), pentafluorophenyl azꢀ
ide37 (5) and (iodoethynyl)benzene28 (12) were prepared according to
literature procedures.
the 31P chemical shift data obtained for solutions of 11 in d2ꢀ
DCM at both 278 K and 295 K to this isodesmic oligomerizaꢀ
tion model. At 295 K, the best fit values for the limiting chemꢀ
ical shift difference between the free and bound states
(+3.3 ppm) and the association constant, K1, (3.9 M–1) both lie
within the error limits of the values obtained for the model
[6•6] dimer at a similar temperature in d2ꢀDCM. However, at
278 K, although the best fit value for the limiting chemical
shift difference between the free and bound states (+2.9 ppm)
is essentially identical to that determined for the [6•6] dimer at
278 K, the best fit value of the association constant, K1, is 9.4
M–1 is somewhat larger than that determined for the [6•6] diꢀ
mer at 278 K (4.0 M–1). However, the two values are still withꢀ
in the 3σ error limits of each other and the difference may
reflect the assumptions made in deriving the isodesmic model
rather than any fundamental changes in the assembly processꢀ
es within the two samples. Diffusion ordered NMR spectrosꢀ
copy also reveals significant differences between the aggregaꢀ
tion behavior of the model compound 6 and 11 in d2ꢀDCM
solution at 298 K. Above a concentration of 50 mM, the diffuꢀ
sion coefficient, D, measured for compound 11 is more than
three times less that that measured for compound 6 under the
same conditions (see Supporting Information for details), sugꢀ
gesting that at higher concentrations, 11 is aggregated signifiꢀ
cantly. These differences in behavior can be visualized
through examination of dried samples of 6 (Figure 5d) and 11
(Figure 5e) using scanning electron microscopy (SEM). These
images provide further evidence for the oligomerization of 11
in d2ꢀDCM solution. Samples of 6 were deposited on the SEM
target from a 20 mM solution in d2ꢀDCM at room temperature
and allowed to dry rapidly in air. This treatment results in the
deposition of µmꢀsized microcrystallites of 6 on the surface of
the target (Figure 5d). By contrast, when the same experiment
was repeated using a 20 mM solution of 11 in d2ꢀDCM at
room temperature, a smooth film (Figure 5e) was deposited
on the surface. This film is extremely smooth over areas larger
than 1500 µm2.
1
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3
4
5
6
7
8
1H, 13C, 19F and 31P NMR spectroscopic data were acquired at a
1
constant temperature of 25 ºC unless stated otherwise. H and 13C
chemical shift are reported in parts per million (ppm) from high to
low field and referenced to the literature values for chemical shift of
the residual nonꢀdeuterated solvent, with respect to tetramethylsilane.
19F NMR chemical shift are referenced to CFCl3 (0.00 ppm). 31P
chemical shift are referenced to PPh3 (–6.00 ppm).
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Electrospray ionization (ESI) spectra were recorded in positive ion
mode, m/z values are reported in Daltons.
SEM samples were airꢀdried and coated with gold (Quorum Q150R
ES) at 10 mA for 30 seconds, SEM images were taken with a field
emission gun electron source running at 5 kV.
Association constants were determined from 31P NMR spectroꢀ
scopic data using WinEQNMR.26
Computational Details.
All calculations were performed using Gaussian0938 suite of proꢀ
grams – revision D.01 was used in all calculations. Calculation
were performed using TPSSh39 functional and the def2ꢀTZVP
basis set40 of Weigend and Ahlrichs. This basis set was introduced
into the calculation using the GenECP keyword and an appropriꢀ
atelyꢀformatted input block for the basis set generated from data
obtained
from
the
Basis
Set
Exchange41
(https://bse.pnl.gov/bse/portal). An effective core potential on
iodine,42 which replaces 28 valence electrons on each iodine atom
was used in all calculations. The calculations were allꢀelectron for
all other elements. All geometries were optimized fully in internal
(keyword: opt) or cartesian (keyword: opt=cartesian) coordiꢀ
nates using the default optimisation protocols within Gaussian09.
Stationary points were characterised by means of a vibrational
analysis (keyword: freq) and zeroꢀpoint energy corrections and
other thermodynamic parameters, used in the calculation of interꢀ
actions energies, were derived43 from this analysis. Population
analyses using the Natural Bond Orbital (NBO) method were
performed using the NBO6 program25 in a twoꢀstage procedure.
The input for NBO6 was generated using Gaussian09 (keyword:
population=nboread) and the .47 file generated by this calcuꢀ
lation was then edited and processed using the gennbo script
provided with the NBO6 distribution. All analyses used the 8ꢀbyte
integer version of NBO6 (6.0.13, dated July 2016) compiled from
source using gfortran (Version 4.4.7). The basis set superposition
error was calculated using the counterpoise method44 as impleꢀ
CONCLUSION
In the expanding lexicon of intermolecular interactions, halꢀ
ogen bonds constitute a particular challenge for chemists who
wish to exploit these interactions for the realization of stable
and functional selfꢀassembled structures in solution. In conꢀ
trast to hydrogen bonds, there are few, if any, empirical rule
sets that exist to guide the design of stable arrays of halogen
bonds in solution. The results presented here highlight the
potential of concatenating halogen bonds into a stable diad,
which follow design rules applied to the more common hydroꢀ
gen bonds. This diad exhibits considerable positive cooperaꢀ
tivity in its assembly and facilitates the assembly of a halogenꢀ
bonded dimer, constructed from neutral XB donors and accepꢀ
tors, that is stable in both d8ꢀtoluene and d2ꢀDCM solution.
The challenge moving forward is to extend these principals to
XB triads and tetrads that are capable of exploiting cooperaꢀ
tive binding to create assemblies in solution that rival those
created using hydrogen bonds.
mented within Gaussian09 (keyword: counterpoise
=
2
).
Halogen bonds were visualized using the NCIPLOT24 program.
SCF densities written as an extended wavefunction file from
Gaussian09 and NCIPLOT used to generate cube files from which
isosurfaces could be visualised using VMD45 with s = 0.5 and an
appropriate colour map (blue (attractive) to red (repulsive))
mapped on to –0.05 < ρ < 0.05.
Synthetic Procedures. (4-(Iodoethynyl)phenyl)diphenylphosphine
oxide (4). NꢀIodomorpholinium iodide (4.97 g, 14.6 mmol) was added
to a solution of (4ꢀethynylphenyl)diphenylphosphine oxide 3 (3.3 g,
10.9 mmol) in 24.0 mL of THF. The mixture thus obtained was stirred
at room temperature for 12 hours. After this time, the reaction was
concentrated under reduced pressure to remove the bulk of the THF
and redissolved in ethyl acetate and, as such, transferred into a sepaꢀ
rating funnel. The organic phase was washed three times with 1 M
sodium thiosulfate aqueous solution then brine, dried over MgSO4,
filtered and concentrated in vacuo. Crystallization of the crude mateꢀ
rial in hot acetonitrile afforded 3.3 g of iodoalkyne 4 as a yellow solid
(7.7 mmol, 53%). Crystals suitable for single crystal Xꢀray diffraction
were obtained upon cooling of a saturated acetonitrile solution.
1H NMR (500.1 MHz, CDCl3): δ 7.65 – 7.58 (m, 6H), 7.56 – 7.52 (m,
EXPERIMENTAL SECTION
General Experimental Methods. All starting material were purꢀ
chased from commercially available sources and used as obtained
unless otherwise specified. 4ꢀ(3,5ꢀDiꢀtertꢀbutylphenyl)ꢀ5ꢀiodoꢀ1ꢀ
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Page 8 of 10
2H), 7.50 – 7.43 (m, 6H). 31P NMR (202.4 MHz, CDCl3): δ 28.7. 13C
mg, 0.12 mmol) for 20 minutes. Iodoalkyne 4 (0.52 g, 1.21 mmol)
NMR (125.7 MHz, CDCl3): δ 132.9 (d, J = 103.4 Hz, 1C), 132.3 (d,
J = 12.9 Hz, 1C), 132.2 (d, J = 3.0 Hz, 1C), 132.1 (d, J = 9.9 Hz, 1C),
132.07 (d, J = 104.3 Hz, 1C), 131.9 (d, J = 10 Hz, 1C), 128.7 (d, J = 10
Hz, 1C), 127.1 (d, J = 2.9 Hz, 1C), 93.21 – 93.20 (m, 1C), 11.37 –
11.32 (m, 1C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for
C20H14IONaP, 450.9701; found 450.9719. M.p. >191.1 ºC dec..
(4-(5-iodo-1-(perfluorophenyl)-1H-1,2,3-triazol-4-
and azide 9 (0.42 g, 1.21 mmol) were dissolved in THF (1.0 mL) and
added in a single portion to the catalyst mixture. After stirring at room
temperature for 12 hours, the reaction mixture was quenched with an
aqueous ammonium hydroxide solution (10%, 1.2 mL) and concenꢀ
trated under reduced pressure. The crude mixture was then redisꢀ
solved in ethyl acetate, washed with water and brine and successively
dried over MgSO4 filtered and concentrated in vacuo. Purification was
achieved by crystallization from hot acetonitrile, affording iodotriaꢀ
zole 6 as a white powder (0.60 g, 0.77 mmol, 64%). Crystals suitable
for single crystal Xꢀray diffraction were obtained upon cooling of a
saturated acetonitrile. 1H NMR (500.1 MHz, CDCl3): δ 8.20 – 8.17 (m,
2H), 7.84 – 7.80 (m, 2H), 7.72 – 7.68 (m, 2H), 7.59 – 7.56 (m, 2H),
7.51 – 7.48 (m, 4H), 4.46 (t, J = 6.6 Hz, 2H), 1.82 – 1.77 (m, 2H), 1.47
– 1.42 (m, 2H), 1.37 – 1.26 (m, 8H), 0.89 (s, 3H). 19F NMR (470.5
MHz, CDCl3): δ −141.47 – −141.59 (m, 2F), −136.88 – −137.01 (m,
1
2
3
4
5
6
7
8
yl)phenyl)diphenyl phosphine oxide (2). Ligand TBTA (37 mg, 0.07
mmol) was stirred in THF (3.0 mL) with copper iodide (13 mg, 0.07
mmol) for 20 minutes. Iodoalkyne 4 (0.30 g, 0.70 mmol) and azide 5
(0.15 g, 0.70 mmol) were then dissolved in THF (1.0 mL) and added
in a single portion to the catalyst mixture. The reaction mixture was
stirred at room temperature for 12 hours and, after this time, quenched
by adding an aqueous ammonium hydroxide solution (10%, 0.7 mL)
and concentrated under reduced pressure. The crude mixture was then
redissolved in ethyl acetate, washed with water, brine and finally
dried over MgSO4, filtered and concentrated in vacuo. Purification by
column chromatography (SiO2, 4:1 DCM: ethyl acetate), followed by
crystallization from hot DCM, afforded the product as a white powder
(0.26 g, 0.41 mmol, 58%). Crystals suitable for single crystal Xꢀray
diffraction were obtained upon cooling of a saturated acetonitrile
solution. 1H NMR (500.1 MHz, CDCl3): δ 8.19 – 8.17 (m, 2H), 7.84 –
7.80 (m, 2H), 7.72 – 7.68 (m, 4H), 7.59 – 7.56 (m, 2H), 7.51–7.48 (m,
4H). 31P NMR (202.4 MHz, CDCl3): δ 28.9. 19F NMR (470.5 MHz,
CDCl3): δ −142.19 – −142.23 (m, 2F), −146.88 – −146.97 (m, 1F),
−158.86 – −158.99 (m, 2F). 13C NMR (125.7 MHz, CDCl3): δ 149.4,
144.9 – 142.6 (m, 1C), 139.3 – 136.9 (m, 1C), 133.9 – 133.1 (m, 1C),
132.8 – 131.8 (m, 5C), 128.7 (d, J = 12.3 Hz, 1C), 127.3 (d, J = 12.1
Hz, 1C), 112.5 – 112.2 (m, 1C), 81.6 – 81.5 (m, 1C), 53.6. HRMS
(ESIꢀTOF) m/z: [M+Na]+ calcd. for C26H14F5IN3NaOP, 659.9737;
found 659.9732. M.p. >204.6 ºC dec..
Octyl 2,3,4,5,6-pentafluorobenzoate (8). Pentafluorobenzoyl chloꢀ
ride 7 (2.00 g, 8.68 mmol) was added to a solution of nꢀoctanol (1.56
g, 11.98 mmol) in 1.5 mL of THF and the mixture thus obtained was
refluxed for 5 hours. After cooling to room temperature, the reaction
mixture was treated with an aqueous saturate solution of NaHCO3,
diluted with ether and, as such, transferred in a separating funnel. The
organic layer was washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. Purification of the product was
achieved by column chromatography of the concentrated crude (SiO2,
4:1 petroleum ether: ethyl acetate) to afford 2.80 g of ester 8 (8.63
mmol, 99%) as a colourless oil. 1H NMR (500.1 MHz, CDCl3): δ 4.36
(d, J = 6.6 Hz, 2H), 1.77 – 1.71 (m, 2H), 1.43 – 1.38 (m, 2H), 1.34 –
1.26 (m, 8H), 0.85 (t, J = 6.7 Hz, 3H). 19F NMR (470.5 MHz, CDCl3):
δ −138.83 – −138.90 (m, 2F), −149.67 – −149.78 (m, 1F), −161.05 –
−161.16 (m, 2F). 13C NMR (125.7 MHz, CDCl3): δ 159.2, 146.6 –
144.3 (m, 1C), 144.2 – 142.0 (m, 1C), 138.9 – 136.7 (m, 1C), 108.7
(td, J = 16.2 Hz and J = 4.0 Hz), 67.1, 31.9, 29.30, 29.26, 28.6, 25.9,
22.8, 14.1. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for C15H17F5NaO2,
347.1046; found 347.1022.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2F). 31P NMR (202.4 MHz, 20 mM, CDCl3):
δ
28.91.
13C NMR (125.7 MHz, CDCl3): δ 158.6, 149.4, 145.7 – 143.4 (m, 1C),
144.0 – 141.8 (m, 1C), 133.4 (d, J = 103.4 Hz, 1C), 132.6 – 131.7 (m,
5C), 128.6 (d, J = 12.0 Hz, 1C), 127.2 (d, J = 12.5 Hz, 1C), 118.4 –
118.1 (m, 1C), 116.3 (t, J = 16.8 Hz, 1C), 80.8, 67.7, 31.8, 29.14,
29.10, 28.4, 25.7, 22.6, 14.1. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd.
for C35H31F4N3NaIPO3, 798.0976; found 798.0959. M.p: >185.0 ºC
dec..
Octyl
2,3,5,6-tetrafluoro-4-(5-iodo-4-phenyl-1H-1,2,3-triazol-1-
yl)benzoate (10). Ligand TBTA (46 mg, 0.09 mmol) was stirred in
THF (3.5 mL) with copper iodide (16 mg, 0.09 mmol) for 20 minutes.
Iodoalkyne 4 (0.19 g, 0.86 mmol) and azide 9 (0.30 g, 0.86 mmol)
were then dissolved in THF (0.5 mL) and added in a single portion to
the catalyst mixture. After stirring at room temperature for 12 hours,
the reaction mixture was quenched with an aqueous ammonium hyꢀ
droxide solution (10%, 0.8 mL) and concentrated under reduced presꢀ
sure. The crude mixture was then redissolved in ethyl acetate washed
with water and brine and successively dried over MgSO4 filtered and
concentrated in vacuo. Purification was achieved by crystallization
from hot acetonitrile, affording iodotriazole 10 as a white powder
1
(0.60 g, 0.77 mmol, 64%). H NMR (500.1 MHz, CDCl3): δ 8.05 –
8.03 (m, 2H), 7.54 – 7.45 (m, 3H), 4.46 (t, J = 6.5 Hz, 2H), 1.83 – 1.77
(m, 2H), 1.48 – 1.42 (m, 2H), 1.37 – 1.22 (m, 8H), 0.89 (t, J = 6.4 Hz,
3H). 19F NMR (470.5 MHz, CDCl3): δ −137.11 – −137.18 (m, 2F),
−141.51 – −141.58 (m, 2F). 13C NMR (125.7 MHz, CDCl3): δ 158.6,
150.6, 145.7 – 143.4 (m, 1C), 144.1 – 141.9 (m, 1C), 129.3, 129.0,
128.8, 127.5, 118.6 – 118.3 (m, 1C), 116.1 (t, J = 16.8 Hz, 1C), 79.4,
67.6, 31.8, 29.14, 29.10, 28.4, 25.7, 22.6, 14.1. HRMS (ESIꢀTOF)
m/z: [M+H]+ calcd. for C23H23F4IN3O2, 576.0766; found 576.0752.
M.p. 109.3 – 111.3 ºC.
Pentane-1,5-diyl bis(2,3,4,5,6-pentafluorobenzoate)46 (12). Penꢀ
tafluorobenzoyl chloride 7 (8.8 g, 38.2 mmol) was added to a solution
of 1,5ꢀpentane diol (2.0 g, 19.2 mmol) in 6.4 mL of THF and the
mixture thus obtained was refluxed for 12 hours. After cooling the
reaction mixture to room temperature, a saturate solution of NaHCO3
was added to neutralize the acid, the mixture was diluted with ethyl
ether and, as such, transferred in a separating funnel. The organic
layer was then washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure to obtain 4.8 g of bisꢀester 12
Octyl 4-azido-2,3,5,6-tetrafluorobenzoate (9). Ester 8 (2.00 g, 6.17
mmol) and sodium azide (0.84 g, 12.9 mmol) were dissolved in 14.0
mL of a 1:1 acetone:water solution and the mixture thus obtained was
heated to 80 ºC for 24 hours. After this time, the reaction was
quenched with water and diluted with diethylether and, as such, transꢀ
ferred in a separating funnel. The organic layer was quenched with
brine, dried over MgSO4, filtered and concentrated in vacuo. Purificaꢀ
tion of the product was obtained by column chromatography (SiO2,
8:1 to 7:3 petroleum ether: DCM) to afford 0.77 mg of 9 as a yellow
1
(9.8 mmol, 51%) as a colorless oil. H NMR (500.1 MHz, CDCl3): δ
4.40 (t, J = 7.1 Hz, 2H), 1.85 – 1.80 (m, 2H), 1.62 – 1.55 (m, 1H). 19F
NMR (376.4 MHz, CDCl3): δ −138.36 – −142.47 (m, 2F), −148.55 –
−148.67 (m, 1F), −160.35 – −160.50 (m, 2F). 13C NMR (125.7 MHz,
CDCl3): δ 159.0, 146.5 – 142.0 (m, 2C), 138.8 – 136.5, 108.2 (dt, J =
15.9 Hz and J = 3.9 Hz, 1C), 66.4, 27.9, 22.2.
1
oil (2.22 mmol, 36%). H NMR (500.1 MHz, CDCl3): δ 4.36 (d, J =
6.6 Hz, 2H), 1.77 – 1.71 (m, 2H), 1.44 – 1.38 (m, 2H), 1.34 – 1.27 (m,
8H), 0.88 (t, J = 7.0 Hz, 3H). 19F NMR (470.5 MHz, CDCl3): δ
−138.87 – −138.97 (m, 2F), −150.99 – −151.09 (m, 2F). 13C NMR
(125.7 MHz, CDCl3): δ 159.6 – 159.5 (m, 1C), 146.5 – 144.2 (m, 1C),
141.7 – 139.5 (m, 1C), 123.3 – 123.1 (m, 1C), 108.2 (t, J = 15.8 Hz,
1C), 67.0, 31.9, 29.3, 29.2, 28.6, 25.9, 22.8, 14.2. HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd. for C15H17F4N3NaO2, 370.1155; found 370.1135.
Pentane-1,5-diyl bis(4-azido-2,3,5,6-tetrafluorobenzoate) (13).
Bisꢀester 12 (3.0 g, 6.1 mmol) and sodium azide (0.84 g, 13.0 mmol)
were dissolved in 14 mL of a 1:1 acetone:water solution and the mixꢀ
ture was heated to 80 ºC for 4 hours. After cooling to room temperaꢀ
ture, the reaction was quenched with water, diluted with diethyl ether
and, as such, transferred in a separating funnel. The organic layer was
washed with brine, dried over MgSO4, filtered and concentrated in
vacuo. No further purification was found necessary: 3.3 g of bisꢀazide
Octyl
4-(4-(4-(diphenylphosphoryl)phenyl)-5-iodo-1H-1,2,3-
1
triazol-1-yl)-2,3,5,6-tetrafluorobenzoate (6). Ligand TBTA (64 mg,
0.12 mmol) was stirred in dry THF (5.0 mL) with copper iodide (23
13 (6.1 mmol, 100%) were obtained as a pale yellow solid. H NMR
(500.1 MHz, CDCl3): δ 4.39 (t, J = 6.3 Hz, 2H), 1.79 – 1.84 (m, 2H),
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The Journal of Organic Chemistry
1.61 – 1.56 (m, 1H). 19F NMR (470.5 MHz, CDCl3): δ −138.82 –
Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi, A.; Resnati, G.; Terꢀ
raneo, G. Chem. Rev. 2016, 116, 2478–2601.
−138.89 (m, 2F), −150.97 – −151.05 (m, 2F). 13C NMR (125.7 MHz,
CDCl3): δ 159.5, 146.5 – 144.3 (m, 1C), 141.6 – 139.5, 123.4 (tt, J =
11.9 Hz and J = 3.0 Hz, 1C), 107.9 (t, J = 15.5 Hz, 1C), 66.4, 28.1,
22.4. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd. for C19H10F8N6NaO4,
561.0516; found 561.0528.
1
2
3
4
5
6
(2) (a) Lunghi, A.; Cardillo, P.; Messina, M. T.; Metrangolo, P.;
Panzeri, W.; Resnati, G. J. Fluor. Chem. 1998, 91, 191–194. (b) Fariꢀ
na, A.; Meille, S.; Messina M. T.; Metrangolo, P.; Politzer, P.; Vecꢀ
chio, G. Angew. Chem. Int. Ed. 1999, 38, 2433–2436. (c) Metrangolo,
P.; Resnati, G. P. Chem. –Eur. J. 2001, 7, 2511–2519. (d) Fox, D. B.;
Liantonio, R.; Metrangolo, P.; Pilati, T.; Resnati, G. J. Fluor. Chem.
2004, 125, 271–281.
5-((4-(4-(4-(diphenylphosphoryl)phenyl)-5-iodo-1H-1,2,3-triazol-
1-yl)-2,3,5,6-tetrafluoro benzoyl)oxy) pentyl 4-(4-(4-(diphenyl phos-
phoryl)phenyl)-5-iodo-1H-1,2,3-triazol-1-yl)-2,3,5,6-
7
8
9
tetrafluorobenzoate (11). Ligand TBTA (47.7 mg, 0.09 mmol) was
stirred in dry THF (3.8 mL) with copper iodide (17.1 mg, 0.09 mmol)
for 20 minutes. Iodoalkyne 4 (0.79 g, 1.80 mmol) and bisꢀazide 13
(0.50 g, 0.93 mmol) were dissolved in THF (5.0 mL) and added in a
single portion to the catalyst mixture. After stirring at room temperaꢀ
ture overnight, the reaction mixture was quenched with an aqueous
ammonium hydroxide solution (10%, 1.8 mL) and concentrated under
reduced pressure. The crude mixture was then redissolved in
ethylacetate and washed with water, brine and dried over MgSO4
filtered and concentrated in vacuo. Purification was achieved by crysꢀ
tallization from hot acetonitrile, affording product 11 as a white powꢀ
der (0.89 g, 0.64 mmol, 64%). 1H NMR (500.1 MHz, CDCl3): δ 8.19 –
8.17 (m, 4H), 7.84 – 7.80 (m, 4H), 7.72 – 7.68 (m, 8H), 7.59 – 7.55 (m,
4H), 7.51 – 7.47 (m, 8H), 4.51 (t, J = 6.6 Hz, 4H), 1.94 – 1.88 (m, 4H),
1.69 – 1.65 (m, 2H). 19F NMR (470.5 MHz, CDCl3): δ −136.87 –
−136.94 (m, 2F), −141.31 – −141.38 (m, 2F). 31P NMR (202.4 MHz,
20 mM, CDCl3): δ 28.96. 13C NMR (125.7 MHz, CDCl3): δ 158.6,
149.4, 145.9 – 143.6 (m, 1C), 144.2 – 141.9 (m, 1C), 133.5 (d, J =
103.4 Hz, 1C), 132.7 (d, J = 10.8 Hz, 1C), 132.3 (d, J = 2.8 Hz, 1C),
132.2 (d, J = 9.9 Hz, 1C), 131.8, 128.7 (d, J = 11.9 Hz, 1C), 127.3 (d, J
= 12.0 Hz, 1C), 118.6 – 118.4 (m, 1C), 116.1 (t, J = 16.6 Hz, 1C), 80.9,
67.2, 28.1, 22.4. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd. for
C59H39F8I2N6O6P2, 1395.0368; found 1395.0328. M.p. >197.2 ºC dec..
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ASSOCIATED CONTENT
Supporting Information
1
Xꢀray data, NMR titration data, H DOSY NMR data, energies
from DFT calculations and coordinates of calculated structures,
NMR spectra. This material is available free of charge the Internet
at http://pubs.acs.org.
Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDCꢀ1514930 (2), CCDCꢀ1514931 (4), CCDCꢀ1514932 (6).
Copies of the data can be obtained free of charge upon application
to the CCDC.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: d.philp@stꢀandrews.ac.uk.
ACKNOWLEDGMENT
We thank the Marie Curie Initial Training Network on Replication
and Adaption in Networks (ReAd) for financial support (early
stage researcher funding to L. M.). We thank Mrs Melanja Smith
and Dr. Filippo Stella for assistance with NMR experiments and
Mr Lars Thode for measuring the association constant for the
complex [PFIB•TPPO] in d8ꢀtoluene.
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